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Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants

Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elus...

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Autores principales: Strohm, Laura, Hu, Zehan, Suk, Yongwon, Rühmkorf, Alina, Sternburg, Erin, Gattringer, Vanessa, Riemenschneider, Henrick, Berutti, Riccardo, Graf, Elisabeth, Weishaupt, Jochen H, Brill, Monika S, Harbauer, Angelika B, Dormann, Dorothee, Dengjel, Jörn, Edbauer, Dieter, Behrends, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258132/
https://www.ncbi.nlm.nih.gov/pubmed/35777956
http://dx.doi.org/10.26508/lsa.202101327
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author Strohm, Laura
Hu, Zehan
Suk, Yongwon
Rühmkorf, Alina
Sternburg, Erin
Gattringer, Vanessa
Riemenschneider, Henrick
Berutti, Riccardo
Graf, Elisabeth
Weishaupt, Jochen H
Brill, Monika S
Harbauer, Angelika B
Dormann, Dorothee
Dengjel, Jörn
Edbauer, Dieter
Behrends, Christian
author_facet Strohm, Laura
Hu, Zehan
Suk, Yongwon
Rühmkorf, Alina
Sternburg, Erin
Gattringer, Vanessa
Riemenschneider, Henrick
Berutti, Riccardo
Graf, Elisabeth
Weishaupt, Jochen H
Brill, Monika S
Harbauer, Angelika B
Dormann, Dorothee
Dengjel, Jörn
Edbauer, Dieter
Behrends, Christian
author_sort Strohm, Laura
collection PubMed
description Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD.
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spelling pubmed-92581322022-07-19 Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants Strohm, Laura Hu, Zehan Suk, Yongwon Rühmkorf, Alina Sternburg, Erin Gattringer, Vanessa Riemenschneider, Henrick Berutti, Riccardo Graf, Elisabeth Weishaupt, Jochen H Brill, Monika S Harbauer, Angelika B Dormann, Dorothee Dengjel, Jörn Edbauer, Dieter Behrends, Christian Life Sci Alliance Research Articles Ubiquilin-2 (UBQLN2) is a ubiquitin-binding protein that shuttles ubiquitinated proteins to proteasomal and autophagic degradation. UBQLN2 mutations are genetically linked to the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). However, it remains elusive how UBQLN2 mutations cause ALS/FTD. Here, we systematically examined proteomic and transcriptomic changes in patient-derived lymphoblasts and CRISPR/Cas9–engineered HeLa cells carrying ALS/FTD UBQLN2 mutations. This analysis revealed a strong up-regulation of the microtubule-associated protein 1B (MAP1B) which was also observed in UBQLN2 knockout cells and primary rodent neurons depleted of UBQLN2, suggesting that a UBQLN2 loss-of-function mechanism is responsible for the elevated MAP1B levels. Consistent with MAP1B’s role in microtubule binding, we detected an increase in total and acetylated tubulin. Furthermore, we uncovered that UBQLN2 mutations result in decreased phosphorylation of MAP1B and of the ALS/FTD–linked fused in sarcoma (FUS) protein at S439 which is critical for regulating FUS-RNA binding and MAP1B protein abundance. Together, our findings point to a deregulated UBQLN2-FUS-MAP1B axis that may link protein homeostasis, RNA metabolism, and cytoskeleton dynamics, three molecular pathomechanisms of ALS/FTD. Life Science Alliance LLC 2022-07-01 /pmc/articles/PMC9258132/ /pubmed/35777956 http://dx.doi.org/10.26508/lsa.202101327 Text en © 2022 Strohm et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Strohm, Laura
Hu, Zehan
Suk, Yongwon
Rühmkorf, Alina
Sternburg, Erin
Gattringer, Vanessa
Riemenschneider, Henrick
Berutti, Riccardo
Graf, Elisabeth
Weishaupt, Jochen H
Brill, Monika S
Harbauer, Angelika B
Dormann, Dorothee
Dengjel, Jörn
Edbauer, Dieter
Behrends, Christian
Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title_full Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title_fullStr Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title_full_unstemmed Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title_short Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD–associated UBQLN2 mutants
title_sort multi-omics profiling identifies a deregulated fus-map1b axis in als/ftd–associated ubqln2 mutants
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258132/
https://www.ncbi.nlm.nih.gov/pubmed/35777956
http://dx.doi.org/10.26508/lsa.202101327
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